The epidermal growth factor receptor (EGFR) is upregulated in squamous cell carcinoma of the head and neck (SCCHN) and has been associated with poor prognosis. We have developed intratumoral EGFR antisense oligonucleotide gene therapy (EGFR AS) as a safe and potentially efficacious treatment for SCCHN as shown in a previous phase I study conducted at the University of Pittsburgh. In the current proposal, we are incorporating EGFR AS in the treatment of potentially curable, locally advanced SCCHN. In recent years, standard therapeutic options for locally advanced SCCHN have improved with the addition of systemic agents to radiation. However, locoregional control and survival remain suboptimal. Moreover, cisplatin-based chemoradiotherapy is associated with a high incidence of serious toxicities. Cetuximab (Erbitux or C225) is a chimerized EGFR monoclonal antibody that has demonstrated survival benefit in a phase III trial in SCCHN and was approved by the FDA for the treatment of locally advanced SCCHN. Radiation plus cetuximab is currently considered standard therapy, especially for patients who are not good candidates for cisplatin chemotherapy. In the proposed phase II study, we plan to evaluate dual EGFR inhibition by adding intratumoral EGFR AS to standard cetuximab with concurrent cetuximab in 30 patients with previously untreated locally advanced SCCHN who either elderly (i.e. 70 years or older) or cisplatin-ineligible. We will evaluate the locoregional progression-free survival (primary endpoint), other efficacy parameters, and toxicities. EGFR AS will be administered weekly by direct intratumoral injection using direct visualization or endoscopy as clinically determined. In order to study the antitumor mechanism of dual EGFR inhibition we will evaluate tumor tissue biomarkers, including EGFR pathway-related signaling proteins, using reverse phase protein microarrays (RPPA) and immunohistochemistry in tumor samples taken before and after therapy. If combination therapy with EGFR AS, cetuximab, and radiation meets the prespecified efficacy criteria will be forwarded to further clinical testing. Our goal is to develop a novel, efficacious and safe combination therapy that will be particularly suitable for patients with SCCHN who cannot tolerate chemotherapy. PUBLIC HEALTH RELEVANCE: This project involves the use of gene therapy against the epidermal growth factor receptor (EGFR), an important molecule for the growth of head and neck cancer cells. We plan to inject an anti-EGFR gene into head and neck cancer tumors during treatment with standard radiation and cetuximab. Our goal is to develop a novel, efficacious and safe combination therapy for advanced head and neck cancer that will be particularly suitable for elderly or frail patients who cannot tolerate chemotherapy. [unreadable] [unreadable] [unreadable]